Going into Sunday's matchup in San Francisco, the Giants defense continues to struggle this year, and the Niners are coming off their most complete game of the season.
For the inconsistent G-Men, this has disaster written all over it.
Here are 10 keys to a New York win on Sunday.
Ahmad Bradshaw got mad at himself when he fumbled away seven points to the Cleveland Browns on Sunday and went on to have his best game as a New York Giant, rushing for 200 yards and a touchdown.
To help the offensive line protect quarterback Eli Manning, the hot-and-cold Bradshaw needs to be more than lukewarm on Sunday.
He doesn't need to run for 200 yards again, but he needs to break the century mark to keep the Niners defensive front honest.
If Bradshaw runs for 100 yards, the G-Men should compete. If not, this could get ugly.
Eli Manning has been, well, Eli Manning.
Spectacular one quarter, horrible the next. Amazing for a half, terrible the next.
The G-Men need "good" Eli to show up early and stick around until the end if they have any shot at beating the 49ers on the road.
If this were January, I might feel differently, but remember: It took Manning 50-plus passes to barely edge the Niners in the NFC championship, and we have yet to see Manning air it out like that with his piecemeal receiving corps.
It's not likely, without Hakeem Nicks, he can come out on top if he plays only half a game against this defense.
The San Francisco 49ers defensive front manhandled New York's O-line last January, and that line is no better today.
This season, the Giants ran roughshod over the Cleveland Browns, and the Carolina Panthers before them, but this is one of the league's premier defensive units.
New York needs time to open holes like it did last week for Ahmad Bradshaw and to help Eli Manning stretch the defense.
Manning was sacked six times in January, and he needs to stay on his feet for New York to have a shot.
The line needs to turn in the performance of the season if the Giants are going to win their first game of the season against a top-10 team.
Corey Webster and the New York Giants secondary may actually be worse this year than last.
Reaching deep into the depth chart will do that to a team, even if you're talking about the Super Bowl champions.
The Giants need to contain Alex Smith, especially keeping him from going more than 40 long to Vernon Davis, Mario Manningham and Randy Moss.
Moss has shown his age this year but still gets up for big games, and this is the biggest.
If Smith completes four passes for 40 yards or more, the Giants go down.
Rueben Randle, the New York Giants' second pick in the draft and a standout at LSU, showed some signs of life last week against the Cleveland Browns.
For the Giants to get some separation for Victor Cruz and Co., New York needs Randle to become an even bigger part of the offense with Hakeem Nicks, who could actually play Sunday but won't be much of a force coming off an injury.
Randle is the real deal, a big target across the middle with good hands a la Keyshawn Johnson.
He needs to grab at least four or five catches—and be a factor on several more snaps—for the Giants to be successful if Nicks does not play.
Frank Gore may not be the threat he once was, but he sure can eat up the play clock and wear down defenses.
New York's defensive front has been solid this season but has struggled, at times, against the run.
To keep 49ers quarterback Alex Smith honest, New York must contain Gore—first at the line, then at the second level, preventing the breakaway run.
Gore has averaged 80-plus yards a game this year and has found the end zone four times. If the G-Men can keep him below that 80-yard mark on Sunday, they could surprise people.
That's a big if.
Vernon Davis killed the New York Giants and just about every team he faced last January.
He's off to another hot start this year, averaging 15.2 yards per catch and ranking right up there with Michael Crabtree with 303 yards receiving.
Davis is the key to the Niners offense, giving Alex Smith a big target over the middle, often bailing him out of trouble when he's under pressure.
Against New York, Davis found the end zone on two of three catches in January. Big Blue will settle for five or six catches if Smith doesn't burn them for 40 yards at a time and take every other pass into the end zone.
The 49ers have their own Devin Hester in a guy named Kyle Williams.
Williams has averaged 35.7 yards per return this year and took one 94 yards that was one tackle from going for a touchdown.
New York's special teams has been suspect this season, though its bend-but-not-break effort on returns has not cost the team a game so far.
This should be a defensive struggle, and a breakdown on special teams could be the deciding factor.
Special teams needs to be on its game.
NaVorro Bowman has been a force to be reckoned with this season, helping lead the San Francisco 49ers to a 4-1 record.
He leads the team in tackles, with 49 total and 27 solos, but just as important is Bowman's effect on opposing teams' game-planning.
Bowman and Patrick Willis have helped the Niners stuff the run week in and week out and will prove a tough test for the rejuvenated Ahmad Bradshaw and a New York Giants O-line that struggled until last week.
Holding their blocks on Bowman is step No. 1 to an effective running game for the Giants. Few teams have been able to do so.
If Eli Manning is going to have a chance against the San Francisco 49ers, the Giants offensive line needs to keep Aldon Smith at bay.
Smith leads the team with 4.5 sacks and has been harassing quarterbacks in the pocket all year.
The Giants have struggled at protecting Manning, though his five sacks are somewhat deceiving. They certainly will fare better against San Francisco if Ahmad Bradshaw stays hot.
The Niners were all over Manning in the NFC Championship Game, which was in doubt until the very end.
Smith and Co. need to be contained for an effective New York passing game.